Neurostimulator

ABSTRACT

Methods and devices for stimulating nerves are disclosed. In one embodiment adapted for stimulating excitable tissue, the invention includes drive circuitry, an acoustic transducer and a pair of electrodes.

PRIORITY CLAIM

This application is a continuation of U.S. patent application Ser. No.12/732,001 filed 25 Mar. 2010, which is a continuation of U.S. patentapplication Ser. No. 10/524,955 filed 3 Feb. 2006, now U.S. Pat. No.7,702,395, which is a national phase application under 35 U.S.C. §371 ofInternational Application No. PCT/US2003/026002 filed 19 Aug. 2003,which claims priority to U.S. Provisional Application No. 60/404,697filed 19 Aug. 2002 and U.S. Provisional Application No. 60/473,240 filed23 May 2003. The entire text of each of the above-referenced disclosuresis specifically incorporated herein by reference without disclaimer.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under grant No. R21RR1330602 and R41 NS42978-01 awarded by the National Institutes ofHealth. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

The present invention relates generally to devices and methods forperforming neural stimulation and more specifically to devices andmethods that employ ultrasound to achieve neural stimulation.

Nerves in higher biological organisms are bundles of long, excitablecells that can extend to meter-order lengths. Cells are referred to asexcitable when they are capable of responding to various electric,chemical, optical, and mechanical stimuli by changing their celltransmembrane potential (TMP). A cell's TMP is a measure of thepotential difference across the cell's membrane. A TMP can be createddue to different concentrations of ions on either side of the membrane.Cells typically maintain lower concentrations of ions inside the cellthan the concentration of ions outside the cell to prevent the cell fromswelling due to osmosis. Therefore, cells typically have a TMP or aredepolarized.

A localized stimulus to an excitable cell, known as an action potential,can affect the cell's TMP. The reduction in TMP causes the cell'smembrane to allow sodium ions to rush into the cell, which furtherreduces the cell's TMP. The reduction of the TMP is known asdepolarization. A cell without TMP will swell due to osmosis, therefore,shortly after the sodium inrush the cell expels potassium through thecell membrane. Reducing the potassium concentration inside the celldecreases charge within the cell and increases the TMP. The process ofrestoring a cell's TMP is known as repolarization.

During the time when the cell is depolarized, it cannot be restimulatedby another action potential. This interval is known as the cell'sabsolute refractory period. The cell's relative refractory period is theinterval from partial to complete repolarization. During this time, thecell can be restimulated, but a higher stimulus is required to producean action potential event, and the response of the excitable cell islower in magnitude.

Nerve cells are a particular type of excitable cell that are typicallycharacterized by a cell body from which extend dendrites and an axon.The long axon is coat in myelin sheaths and axon terminals extend fromthe end of the axon. When the nerve cell is stimulated, a depolarizationwave travels down the axon to the axon terminals. The axon terminalsrespond to the depolarization wave by releasing specialized chemicalsknown as neurotransmitters. The neurotransmitters bind to receptors inthe dendrites of adjacent nerve cells and depending on the type ofreceptor that is activated, will either excite or inhibit the generationof an action potential in the adjacent cell. In this way, signals arepassed from one nerve cell to another and enable impulses to be carriedalong nerve fibers.

Neurostimulation is a term used to describe the artificial excitation orinhibiting of nerve cells. Neurostimulation is thought to be desirableas either a tool for simulating nerve function or for inhibiting theflow of information to the brain (e.g. blocking pain impulses). Theability to selectively stimulate specific nerve fibrils in a complexnerve bundle containing thousands, is a long sought capability inbiomedical research. One method has been to try and stimulate the nervesusing an electrode. However, placing an electrode in contact with thedesired nerve fibril can be invasive. Alternatively, a nerve cuffelectrode can be used. Nerve cuff electrodes typically involve placingmultiple electrodes around the nerve to create an electric fielddesigned to stimulate a specific nerve fiber.

SUMMARY OF THE INVENTION

Methods and apparatus are described that enable the stimulation ofneurons using a combination of ultrasound and electric currents. In oneaspect of the invention, high frequency ultrasound and electric currentsare used to stimulate neurons. In a further aspect of the invention,ultrasound is used to excite devices that include piezoelectricmaterials, which generate electric currents for stimulating neurons.

In one embodiment, the invention includes drive circuitry, an acoustictransducer and a pair of electrodes. In addition, the drive circuitrycan be configured to drive the acoustic transducer to generate apressure wave, the acoustic transducer can be positioned to direct thepressure wave at excitable tissue and the drive circuitry can beconfigured to generate stimulating current between the pair ofelectrodes.

In a further embodiment, the pair of electrodes are implemented using apiezoelectric chip, the drive circuitry is configured to drive theacoustic transducer to generate a pressure wave and the acoustictransducer is positioned to direct the pressure wave towards thepiezoelectric chip.

In another embodiment, the piezoelectric chip includes a piezoelectricelement having at least two opposite surfaces, rectifying circuitry, abiocompatible coating surrounding the piezoelectric element and thediode and an electrode located adjacent each of the opposite surfaces,where each electrode is partially contained by the biocompatiblecoating. In addition, the piezoelectric element can include zirconatetitanate (PZT). In a still further embodiment, the piezoelectric elementcan include polyvinylidene fluoride (PVDF).

In yet another embodiment, the invention can include additionalpiezoelectric chips. In addition, each of the piezoelectric chips canhave a different resonant frequency and the drive circuitry can beconfigured to drive the acoustic transducer at the resonant frequency ofone of the piezoelectric chips.

In a still further embodiment again, the drive circuitry includes apulse generator, a function generator connected to the pulse generatorand amplifier circuitry connected to the function generator. Inaddition, the amplifier circuitry can include a drive amplifier and a RFamplifier.

In one embodiment, the method of the invention includes applyingstimulating ultrasound to tissue and applying a stimulating electriccurrent to the tissue.

In another embodiment, the method of the invention includes directingpressure waves at a piezoelectric chip located proximate excitabletissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block view of an embodiment of a neurostimulator inaccordance with the present invention;

FIG. 2 is a schematic diagram that schematically illustrates anembodiment of a neurostimulator in accordance with the presentinvention;

FIG. 3 is a flow chart illustrating a method in accordance with thepresent invention that can be used to either stimulate or inhibit thecreation of a compound action potential in a nerve fiber;

FIG. 4 is a graph showing a compound action potential generated inresponse to neurostimulation in accordance with the present invention;

FIG. 5 is a graph comparing the compound action potentials generatedusing electrical stimulation alone and using ultrasound and electricalstimulation in accordance with an embodiment of the present invention;

FIGS. 6A and 6B are schematic diagrams illustrating the effect of thewavelength of pressure waves generated in accordance with an embodimentof the present invention on ion channels in nerve cell membranes;

FIG. 7 is a schematic view of an embodiment of a neurostimulator inaccordance with the present invention that uses an embeddedpiezoelectric chip to generate electric fields;

FIG. 8 is a schematic view of an embodiment of a piezoelectric chip inaccordance with the present invention;

FIG. 9 is a flow chart illustrating a method in accordance with thepresent invention for performing neurostimulation using a piezoelectricchip that is capable of generating an electric field when illuminated byultrasound;

FIG. 10 is a graph showing the generation of a compound action potentialin response to neurostimulation via an electric field generated by apiezoelectric chip in accordance with the present invention; and

FIG. 11 is a schematic view illustrating the excitation of a number ofpiezoelectric chips with ultrasound energy in accordance with anembodiment of a the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Turning now to the drawings, novel approaches to achievingneurostimulation are presented involving devices and methods thatutilize electric currents and/or ultrasound. In one embodiment, highfrequency ultrasound is used in combination with electric currents toachieve neurostimulation. In another embodiment, piezoelectric chipsimplanted proximate a nerve fiber are used to convert ultrasound energyinto sufficient electric current to achieve neurostimulation.

Turning now to FIG. 1, a neurostimulator in accordance with the presentinvention is illustrated. The neurostimulator 10 includes drivecircuitry 12 that is connected to an ultrasound transducer 14 and acurrent stimulator 16. The drive circuitry includes a pulse generator 18that is connected to a function generator 20 and the current stimulator16. The function generator 20 is connected to a drive amplifier 22. Thedrive amplifier is connected to an RF amplifier 24, which provides anoutput to the ultrasound transducer 14. The ultrasound transducer isfocused at a nerve fiber 26 and the current stimulator is connected toelectrodes 28 that are positioned proximate the nerve fiber.

In embodiments, where the nerve fiber is contained within a subject'sbody, the electrode may be located external to the subject or internalto the subject. Where the electrodes are external to the subject, theelectrodes are typically positioned around the ultrasound transducer.Where the electrodes are internal to the subject, one electrode istypically placed as close to the nerve as possible and another electrodeis placed on the other side of the stimulating pressure wave generatedby the ultrasound transducer. Although other configurations that createsufficient electric currents in the region the ultrasound is stimulatingcan also be used.

The drive circuitry can generate electric signals that drive theultrasound transducer and the current stimulator. The ultrasoundtransducer can use these signals to generate pressure waves forstimulating nerve fibers. The electrode can also stimulate nerve fibersby generating electric currents. In one embodiment, the pulse generatorprovides a pulse to the function generator and the current stimulator.The pulse can trigger the function generator to produce a high frequencysinusoidal signal, which is then provided to the drive amplifier. Thedrive amplifier and the RF amplifier combine to increase the power ofthe high frequency sinusoidal signal to the level required for theultrasound transducer to generate pressure waves of sufficient power. Apulse can also prompt the current stimulator to generate a signal, whichgenerates a desired electric current between electrodes. In oneembodiment, the combination of the pressure waves generated by theultrasound transducer and the electric currents generated by theelectrodes cause a compound action potential in the nerve fiber. Inanother embodiment, the combination of the pressure waves generated bythe ultrasound transducer and the electric currents generated by theelectrodes can inhibit the generation of a compound action potential inthe nerve fiber.

A neurostimulator in accordance with the present invention isillustrated in FIG. 2. The neurostimulator 10′ includes a computer 38.The computer is connected to an isolated current stimulator 40 and an RFswitch 42. The isolated current stimulator is connected to electrodes44. The RF switch is connected to a signal generator 46 and a driveamplifier 48. The output of the drive amplifier is provided to anultrasound transducer 50. The ultrasound transducer is focused on a frognerve 52 that is contained in a chamber 54 filled with Ringer's solution56.

In one embodiment, the computer uses a software package such as LABVIEW,created by National Instruments Corporation of Austin, Tex. to generatestimulation trigger pulses. The computer can generate the trigger pulsesusing an output card such as a model DAQ1200 card manufactured byNational Instruments Corporation. The trigger signal can be used tosynchronize current delivery from the isolated current stimulator, whichcan be implemented using a model 2100 manufactured by A-M Systems, Inc.of Sequim, Wash. The output of the isolated current stimulator isprovided to the electrodes, which can be 500 μm silver wire stimulatingelectrodes spaced by 3 mm. Although in other embodiments, otherelectrodes suitable for use in biomedical applications involving thegeneration of electric currents can be used. The output of the signalgenerator can be provided to the RF switch, which is gated to pass theRF signal in response to trigger pulses from the computer.

In one embodiment, the signal generator can be implemented using a Model8657A manufactured by the Hewlett Packard Company of Palo Alto, Calif.and the RF switch can be implemented using a Model 50S-348 manufacturedby JFW Industries, Inc. of Indianapolis, Ind. The output of the RFswitch is provided to the drive amplifier, which can drive theultrasound transducer.

In one embodiment, the drive amplifier is implemented using a Model 3032manufactured by Ophir RF of Los Angeles, Calif. and the ultrasoundtransducer is produced by a miniature transducer manufactured by ValpeyFisher Corporation of Hopkinton, Md. that has a 1 mm diameter, is 125 μmthick, is lightly damped and has a lithium niobate radiating element.

In addition to the embodiments described above, one of ordinary skill inthe art would appreciate that other components that perform similarfunctions and different configurations of components can be used thatare capable of providing appropriate drive signals to electrodes and anultrasound transducer. In addition, one of ordinary skill in the art canappreciate that the dimensions and materials used in the construction ofthe ultrasound transducer are a function of the wavelength of thepressure waves that are sought to be generated by the transducer. Adiscussion of the variation in compound action potential responseassociated with the wavelength of the pressure waves generated by thepressure transducer is provided below.

A process in accordance with the present invention for stimulating anerve fiber is illustrated in FIG. 3. The process 60 includesstimulating the nerve fiber with ultrasound 62 and stimulating the nervefiber with an electric current 64. In one embodiment, the ultrasoundstimulation is applied for a time period and the electrical stimulationis applied at the end of the time period.

A graph is illustrated in FIG. 4 that shows the timing of theapplication of ultrasound stimulation, electrical stimulation and thesubsequent generation of a compound action potential. The graph 70includes 3 plots. The uppermost plot 72 is of the ultrasound triggerpulse. For the duration of the ultrasound trigger pulse, ultrasoundstimulates the nerve fiber. The middle plot is of the electricalstimulation pulse 74. The electrical stimulation pulse is used togenerate an electric current for stimulating the nerve fiber. Theelectrical stimulation pulse is triggered at approximately the end ofthe ultrasound trigger pulse. The lower plot 76 shows the nerveresponse. The application of the electrical stimulation pulse creates acompound action potential.

In the illustrated embodiment, an ultrasound pre-pulse is used tostimulate the nerve fiber. Observations have shown that ultrasound canbe nominally effective in causing changes in nerve excitability forseveral milliseconds after cessation of an ultrasound pre-pulse. Thetime that ultrasound causes an effect on nerve fibers varies with theultrasound frequency, pulse duration, duty cycle and other factors.Typically, the nerve will remain stimulated for a period of between 3milliseconds and several seconds.

In other embodiments. simultaneous application of ultrasound andelectrical stimulation is effective in generating a compound actionpotential. Alternately, other embodiments of the invention can useultrasound pulses to provide an initial stimulation and then following adelay. trigger an action potential using electrical stimulation.

In the embodiment illustrated in FIG. 4. an ultrasound pulse with afrequency of 20 MHz and an electrical stimulation pulse of less than 1mA were used to stimulate the nerve fiber. When ultrasound is used tostimulate a nerve fiber, the amplitude of the electrical stimulationrequired to generate a compound action potential can be reduced.Alternatively, the magnitude of the compound action potential can beincreased.

A graph is illustrated in FIG. 5 that shows the effect of usingultrasound to stimulate a nerve in addition to electrical stimulation.The graph 80 includes two plots. The first plot 82 shows the compoundaction potential generated when electrical stimulation alone is used tostimulate an in-vitro frog sciatic nerve. The second plot 84 shows thecompound action potential generated when ultrasound and electricalstimulation are used to stimulate the same nerve. The magnitude of thecompound action potential increases with the addition of ultrasoundstimulation. In the illustrated embodiment, the applied ultrasound was apulse of a duration of 10 ms and a peak power of approximately 100W/cm². In other embodiments, fully saturated nerve responses have beenobtained using ultrasound and an electrical stimulus that would recruitas little as 10% of the cells in the nerve fiber without the use ofultrasound.

Embodiments of the present invention, as described above, are capable ofusing a variety of frequencies of ultrasound to stimulate a nerve fiber.Some embodiments are effective at generating compound action potentialswhen ultrasound with a frequency of between 15 MHz and 100 MHz is used.Frequencies outside this range can also be effective in generatingaction potentials, but can require higher power levels to achieve thesame effectiveness. The following table shows the effect of thefrequency of the ultrasound used to stimulate a nerve on the magnitudeof the compound action potential achieved using a fixed electricalstimulating pulse.

TABLE 1 Effect of Frequency on Ultrasound Evoked Bioelectric StimulationEvents Relative Bioelectric Effect Ultrasound Number of of UltrasoundStimulation Frequency Trials Weighted for Power Compared to 17.5 MHz17.5 MHz 10 1.0 56.5 MHz 10 3.4 ± 1.2   93 MHz 2 3.0 ± 0.7

The above table illustrates that the magnitude of a generated compoundaction potential varies with frequency. A theory has been proposedconcerning the effectiveness of various ultrasound frequencies atgenerating compound action potentials. Devices and methods of thepresent invention do not in any way rely upon theories presented here inorder to be effective in generating compound action potentials. However,applicants propose that applying pressure forces to ion channels in cellmembranes decreases the potential required to open the ion channels andstimulates the creation of an action potential.

The effect of pressure on an ion channel is illustrated in FIG. 6A. Anion-channel 90 is illustrated that is not exposed to ultrasound. The ionchannel is closed and creates an effective barrier between the interiorof the cell and extracellular fluids. A second ion channel 92 isillustrated. The second ion channel is stretched due to a pressure wavetraveling through the cell. The pressure wave stretches the cellmembrane, which opens the ion channel and allows ions to pass in and outof the cell.

The impact of wavelength (i.e. frequency) on the ability of a pressurewave to open ion channels in cell membranes is illustrated in FIG. 6B.Two nerve fibrils are illustrated. The first nerve fibril 100 is excitedusing a 100 MHz ultrasound transducer 102 in accordance with the presentinvention. The short wavelength of the pressure wave (not to scale)generated by the 100 MHz ultrasound transducer is comparable to thedimensions of the fibril and the fibril's membrane. The second nervefibril 104 is excited using a 10 MHz ultrasound transducer. The longerwavelength (not to scale) of the pressure wave generated by the 10 MHzultrasound transducer results in a pressure wave that is several ordersof magnitude larger than the size of the nerve fibril. Stretching ofcell membranes results from pressure differentials at differentlocations in the pressure wave. When a pressure wave has a wavelength ofa similar order to a nerve fibril, the forces experienced by the cellmembrane of the fibril will be significant because the entire pressuredifferential between the peak and the trough of the pressure wave isexperienced by the cell.

When constructing embodiments of the present invention in accordancewith the techniques described above, the frequency of the ultrasoundchosen is important. Ultrasound waves in the VHF region (30-100 MHz) aremore strongly absorbed by tissue and have less penetration compared tothe diagnostic frequencies below about 10 MHz. Ultrasound intensityalong a beam path declines exponentially. Experiments have determinedthat the effective penetration depths in tissue to the 10% intensitypoint will be on the order of a centimeter at 30 MHz and millimeters at100 MHz. Therefore, systems in accordance with the present inventionthat require ultrasound to penetrate through significant amounts of boneor flesh to stimulate a neuron can be subject to a tradeoff between thedesire to increase frequency to produce the strongest stimulatory effectand trying to reduce frequency in order to penetrate to the requireddepth.

The penetration depth of a particular frequency of ultrasound can beincreased by using lenses to focus the ultrasound generated by anultrasound transducer. A focused wave can spread a large amount ofenergy over a large area at the surface and enable a significant amountof that energy to converge on the focal point, despite absorption.

In one embodiment, lenses for focusing ultrasound can be constructedusing molded epoxies that are applied to the ultrasound transducer.Focal spot sizes of just a few wavelengths are possible and can giveenergy concentration ratios of several hundred. This offers thepotential to obtain a much greater penetration depth when the targetarea is very small. Additionally, ultrasound can be projected into tightbeams and reach effective intensity at some distance from the transducerface.

The characteristics of the ultrasound pulses are important in achievingneurostimulation. In one embodiment, ultrasound pulses having a pulselength of between 300 μs and 10 ms are used and the pulses are repeatedwith a repetition rate of between 1 pulse per second and 10 pulses persecond. When the length of the pulse is decreased, the effectiveness ofthe ultrasound in stimulating a nerve fiber is decreased. Increasing theduration of the pulse beyond 50 ms can have the effect of causing nervedamage due to the amount of energy transferred by the pulses.

As observed previously, embodiments of the present invention may be usedto inhibit compound action potentials as an alternative to stimulatingcompound action potentials. Experimental results have yielded theconclusion that the repetition rates and duration of ultrasound pulsesdetermine whether a stimulatory or inhibitory effect is achieved. Inaddition, results have also shown that the pulse characteristics thatwill achieve stimulatory effects and inhibitory effects are repeatablefor each preparation. However, results have also shown that thecharacteristics vary from preparation to preparation. Therefore, one ofordinary skill in the art would appreciate that varying thecharacteristics of ultrasound pulses may be required for differentsubjects in order to achieve the desired stimulatory or inhibitoryeffect.

In several of the embodiments described above penetration depth can be aproblem, because the ultrasound transducers are located external to thesubject. In other embodiments, one or more ultrasound transducers can belocated on a nerve cuff electrode. Locating ultrasound transducers on anerve cuff electrode enables focused ultrasound that can target specificfibers. In one embodiment, a nerve cuff is used that includes an arrayof ultrasound transducers of sub-millimeter size around thecircumference of the nerve cuff and each ultrasound transducer can beelectrically addressed.

Many neurostimulation systems require the generation of electric fieldsusing electrodes that are connected via wires to driving circuitry. Whena nerve fiber located within a subject's body is sought to bestimulated, electrodes are typically either implanted into the subjector attached to the surface of the subject's body. Implanting ofelectrodes is invasive and typically requires that leads connecting theelectrodes to external driving circuitry emerge from the subject's body.When electrodes are located on the surface of the subject, theelectrical field required to stimulate the nerve fiber may exceed thepain threshold of the skin.

A neurostimulator that uses an implanted piezoelectric chip as anelectrode is illustrated in FIG. 7. The neurostimulator 200 includesdriving circuitry 202 connected to an ultrasound transducer 204 and atleast one piezoelectric chip 206. The driving circuitry includes a pulsegenerator 208 that is connected to a function generator 210. Thefunction generator is connected to a drive amplifier 212, which in turnis connected to an RF amplifier 214. The output of the RF amplifier isprovided to the ultrasound transducer. The piezoelectric chip is locatedproximate a nerve fiber 216.

The drive circuitry 202 generates a drive signal that is provided to theultrasound transducer. The drive signal enables the ultrasoundtransducer to generate a desired pressure wave in a manner similar tothat described above in relation to FIG. 1. The ultrasound transducer ispositioned to create a pressure wave that is incident on thepiezoelectric chip. The excitation of the piezoelectric materials in thepiezoelectric chip generates an electric current that can then be usedto stimulate an action potential or inhibit the creation of an actionpotential in a nerve fiber.

The ability to ultrasonically cause nerve action events using implantedpiezoelectric chips can depend on the physics of piezoelectric materialsused in the piezoelectric chips, electric field propagation innonhomogeneous volume conductors, as well as acoustics. Ultrasoundpulses averaging an intensity of 10-100 mW/cm² in the range of 2.5-7.5MHz can evoke milliamperes from small chips of piezoelectric materialsimmersed in a medium having a physiologic conductivity.

Electrical waves at MegaHertz ultrasound frequencies are relatively longin wavelength compared to body dimensions. This means that thepiezoelectric chip can be considered as a near field electrical sourcecoupled by a complex impedance to electrodes.

An embodiment of a piezoelectric chip in accordance with the presentinvention is illustrated in FIG. 8. The piezoelectric chip 220 includesa thin piezoelectric element 222 to which a diode 224 is attached. Thepiezoelectric element and the diode are encased in a biocompatiblecoating 226. A pair of electrical contacts 228 are partially embeddedwithin the biocompatible coating at opposite ends of the piezoelectricchip.

The piezoelectric element can be constructed from a piezoelectricmaterial, which is a material that generates a current when pressure isapplied to the surface of the material. This class of materials includespolymers like polyvinylidene fluoride (pVDF), ceramics like leadzirconate titanate (PZT) and crystals like quartz. When piezoelectricmaterials are placed in a volume-conducting medium so that the surfacesof the material contact the solution, the generated potentials can besignificant and sufficient to stimulate compound action potentials fromnerve fibers.

When choosing a piezoelectric material to construct the piezoelectricelement, the amount of energy in the pressure wave incident on thepiezoelectric element that is converted into an electric field isimportant to the efficiency of the system. The acoustic impedance of thepiezoelectric material relative to tissue determines how much ultrasoundenergy is actually absorbed and turned into charge. The rest of theenergy is reflected at the interface between the sound transport mediumand piezoelectric material. This relationship can be determined fromR=[(Z1−Z2)/(Z1+Z2)]2

Where R is the fraction of incident sound power reflected from thesurface of PZT while the remainder enters, and

Z1 and Z2 are the acoustic impedance's of the materials.

In tissue, calculations estimate that embodiments of the presentinvention that use PZT will reflect approximately 90% of incidentenergy. Embodiments that use PVDF are estimated to reflect approximately11% of incident energy, because the PVDF polymer has an acousticimpedance much closer to that of tissue.

In practice, factors such as electrical power transfer) as defined bythe electrical port impedance of the materials) and how materials matchto tissue electrical impedance at a desired ultrasound frequency caninfluence design decisions. A piezoelectric material's dielectricconstant and its self-capacitance are significant factors in determiningport impedance. For low impedance conductive media such as tissue, thelower port impedance of PZT can make it preferable to a material with ahigher port impedance such a PVDF, despite the greater theoreticalefficiency of PVDF in converting energy from a pressure wave into anelectric field.

In one embodiment of a piezoelectric chip adapted for use inside humantissue, the

piezoelectric element is constructed using a piece of PZT that has athickness of 100 μm, a width of 1 mm and a length of 3 mm. Apiezoelectric element with these dimensions can be inserted into asubject using a 16 gauge needle. In other embodiments, piezeo elementscan be constructed using pieces of PZT of various sizes. The larger thevolume of the piezoelectric element, the greater the current that can begenerated using the piezoelectric element In one embodiment, thepiezoelectric element is constructed using the material PZT-5Amanufactured by Boston Piezo-Optics, Inc of Bellingham, Mass. Otherpiezoelectric materials can also be used, which would be dimensionedaccording to the voltage and current requirements of the particularapplication. Examples of other piezoelectric materials that could beused include any piezoceramic, Lithium Niobate, quartz, LeadMetaniobate, Lead Titanate, Tourmaline or any other material that willgenerate a potential when excited by a pressure wave.

In other embodiments, the piezoelectric element can be constructed usingmultiple pieces of piezoelectric material connected in electrical seriesto increase the potential generated by the piezoelectric element by afactor proportionate to the number of pieces of piezoelectric materialand to decrease the current generated by the same factor. Theseembodiments can be useful in circumstances where the electroderesistance is high and additional voltage is required to generate astimulating current.

It is well known that nerves respond to electrical impulses over certainranges of duration and amplitude. The frequency of the electricalcurrents generated by piezoelectric chips as a result of stimulationusing ultrasound are typically of a frequency that is too high tostimulate a compound action potential. In the illustrated embodiment, adiode is used to rectify the current generated by the piezoelectricelement. The combination of half-wave rectification and the capacitanceof the two electrodes in the piezo chip (i.e. the electrode equivalentcapacitance) smooth the generated current to provide a pulse with aduration proportionate to the duration of the ultrasound pulse used tostimulate the piezoelectric element. Therefore, appropriate choice ofthe ultrasound pulse duration can ensure that the generated current iscapable of stimulating a compound action potential. In embodiments,where the electrode equivalent capacitance is insufficient to providethe required smoothing, a capacitor can be connected between theelectrodes to increase the electrode equivalent capacitance. In oneembodiment, a 1n34A industry standard germanium diode is used to providehalf wave rectification. In other embodiments, Shotcky diodes, silicondiodes or an integrated diode bridge could be used to rectify thecurrent generated by the piezoelectric element. In other embodiments,other circuits that convert the current generated by the piezoelectricelement to a current capable of stimulating a compound action potentialcan be used.

In one embodiment the biocompatible coating serves to insulate theelectrical interconnects within the piezoelectric chip and isconstructed using a polyimide such as PYRALIN 2721 manufactured by E.I.DuPont Nemours and Company of Wilmington, Del. In other embodiments,other coatings such as biocompatible epoxies or biocompatible polymersthat are preferably transparent to sound can be used in the constructionof a biocompatible coating. When a photoresist material such as PYRALINis used in the construction of the piezoelectric chip, the biocompatiblecoating can be applied to the entire chip and then the electrodes can bepartially exposed using photoresist techniques.

In other embodiments, the biocompatible coating can be loaded usingadditives such as Tungsten that increase the acoustic impedance of thebiocompatible coating to enable more efficient acoustic power transferfrom the tissue medium to the piezoelectric element. In addition, theamount of energy in a pressure wave that is converted into electricalenergy by a piezoelectric chip in accordance with the present inventioncan be increased by acoustic impedance matching the thickness of thebiocompatible coating with the frequency of the pressure waves.Typically, impedance matching can be achieved by using a biocompatiblecoating having a thickness that is approximately equal to one quarter ofthe wavelength of the pressure waves being used to stimulate thepiezoelectric chip.

The electrodes can serve the function of transferring electrical currentfrom the piezoelectric element to stimulate an ionic current flow in aconductive fluid and in one embodiment are constructed using a chromiumbased stainless steel alloy such ELGILOY manufactured by ElgiloySpecialty Metals in Elgin, Ill. In other embodiments, otherbiocompatible electrode materials such as platinum, silver, iridiumoxide, tantalum can be used in the construction of the electrodes.

A flowchart for stimulating a nerve fiber in accordance with the presentinvention is illustrated in FIG. 9. The process 240 includes implantinga piezoelectric chip proximate the nerve fiber, generating a pressurewave incident on the piezoelectric chip 244 and using an electriccurrent generated by the piezoelectric chip to stimulate the nerve fiber246.

In one embodiment, the piezoelectric chip is designed to be small enoughto be implanted close to the nerve fiber using a standard gauge syringe.The pressure wave incident on the piezoelectric chip can have similarfrequencies to a pressure wave generated by a medical diagnostic system,as described above. The pulse duration and amplitude of the pressurewave is typically chosen such that a piezoelectric chip can generate acurrent capable of stimulating a compound action potential in the mannerdescribed above. In several embodiments, a modified medical imagingultrasound transducer can be used that is capable of locating thepiezoelectric chips using reflected ultrasound and then switching modesto stimulate the located chips using appropriate ultrasound pulses.

In other embodiments other frequencies and powers can be used dependingon the size and the type of piezoelectric chip, the distance of thepiezoelectric chip from the nerve fiber and the electric currentrequired to generate a desired compound action potential. The electriccurrent generated by the piezoelectric chip in response to excitation bypressure waves is dependent on the factors described above. In otherembodiments, a combination of an electric current generated by thepiezoelectric chip and pressure waves generated by an ultrasoundtransducer can be used to stimulate the nerve fiber (see above).

A graph showing the generation of a compound action potential inresponse to an electric field generated by a piezoelectric chip, onwhich a pressure wave is incident is illustrated in FIG. 10. The graph250 includes two plots. The first plot 252 shows the ultrasoundstimulated electric field generated by the piezoelectric chip. Thesecond plot 254 shows the compound action potential generated inresponse to the stimulating electric field.

The resonance of a piezoelectric material is a function of the ratio ofthe ultrasound wavelength to the material thickness. A thickness ofpiezoelectric material. equal to a half-wavelength of the incidentultrasound tends to increase the power transferred to the piezoelectricmaterial and increase the voltage output by the piezoelectric chip. Thisis particularly true of high-Q piezoceramics like PZT, whichmechanically ring at their natural resonant frequency. Therefore, theelectric currents generated by piezoelectric chips will tend to berelatively larger at their resonant frequencies. This means that anarray of piezoelements, each having a different natural frequency, canbe implanted into the body and thus be actuated individually byselection of applied ultrasound frequency.

The use of a multiple piezoelectric chips to selectively stimulate nervefibers in accordance with the present invention is illustrated in FIG.11. The neurostimulator includes an ultrasound source that is capable ofgenerating multiple frequencies of ultrasound and a first piezoelectricchip 264 and a second piezoelectric chip 266. The first and secondpiezoelectric chips are implanted in tissue proximate a nerve bundle 270including a number of nerve fibers 272. Each piezoelectric chip can beconstructed to have a different resonant frequency. Generating pressurewaves with a frequency corresponding to the resonant frequency of one ofthe piezoelectric chips results in that piezoelectric chip generating asignificantly stronger electric field. Therefore, different frequenciesof ultrasound can be used to selectively stimulate different nervefibers using different piezoelectric chips. Alternatively, multiplechips with the same resonant frequency can be selectively stimulated byfocused pressure waves or simultaneously stimulated using a singleultrasound transducer.

In one embodiment, neurostimulators in accordance with the presentinvention can be used to stimulate the pudental nerve. Urinalincontinence can be combated by stimulation of the pudental nerve.Patients are often reluctant to undergo treatment using conventionalneurostimulators, because the intensity of the required electriccurrents can cause pain and/or discomfort. Therefore, neurostimulationin accordance with the present invention involving the use of ultrasoundstimulation can reduce the intensity of electric currents requiredand/or the use of an implanted piezoelectric chip as an electrode canreduce the electric field required at the surface of the subject's bodyand enable treatment without discomfort.

The same advantages are also available when embodiments of the presentinvention are used as a substitute for conventional transcutaneouselectronic nerve stimulators (TENS). Pulsed electrical currents in themilliampere range can block pain impulses traveling up the spine. Thisworks by stimulating large fast nerve fibers, which block painsensations from slower sensory nerves. Conventional TENS devices cancause a tolerable but uncomfortable shocking sensation at theelectrodes, because the electrical currents required to be effective arethemselves not far from the threshold that produces pain from skinreceptors. As described above, embodiments of the present invention canbe used to provide the benefits of TENS while reducing the likelihood ofpain or discomfort.

Although the foregoing embodiments are disclosed as typical, it will beunderstood that additional variations, substitutions and modificationscan be made to the system, as disclosed, without departing from thescope of the invention. For example, animal subjects may be used inaddition to human subjects, when applying neurostimulation in accordancewith the present invention. In addition, the discussion presented abovehas focused on neurostimulation. Other embodiments of the presentinvention may be used to stimulate various excitable tissue types suchas muscle tissue.

The invention claimed is:
 1. An implantable neurostimulator comprising:a first electrode electrically coupled to a first piezoelectricmaterial; a second electrode electrically coupled to the firstpiezoelectric material; a third electrode electrically coupled to asecond piezoelectric material; a fourth electrode electrically coupledto the second piezoelectric material; a biocompatible coatingsurrounding first and second piezoelectric materials; where the firstpiezoelectric material is configured to provide an electrical potentialto biological tissue through the first and second electrodes in responseto an ultrasound signal; where the second piezoelectric material isconfigured to provide an electrical potential to biological tissuethrough the third and fourth electrodes in response to an ultrasoundsignal; where the first and second piezoelectric materials havedifferent resonant frequencies; and where the first and secondelectrodes protrude through the biocompatible coating.
 2. Theimplantable neurostimulator of claim 1, where the biocompatible coatingis configured to reduce an immunological response to the implantableneurostimulator when the neurostimulator is implanted in biologicaltissue.
 3. The implantable neurostimulator of claim 1, where thebiocompatible coating is configured to protect the implantableneurostimulator from exposure to biological tissue.
 4. The implantableneurostimulator of claim 1, where the biocompatible coating isconfigured to protect biological tissue from the implantableneurostimulator.
 5. The implantable neurostimulator of claim 1, wherethe biocompatible coating is configured to enable efficient acousticpower transfer from biological tissue to the first piezoelectricmaterial.
 6. The implantable neurostimulator of claim 5, where thebiocompatible coating is effectively transparent to ultrasound.
 7. Theimplantable neurostimulator of claim 5, where the biocompatible coatingis loaded with an additive.
 8. The implantable neurostimulator of claim7, where the additive is tungsten.
 9. The implantable neurostimulator ofclaim 5, where an acoustic impedance of the biocompatible coating ismatched with an acoustic impedance of the first piezoelectric material.10. The implantable neurostimulator of claim 9, where the thickness ofthe biocompatible coating is approximately one quarter of the wavelengthof a pressure wave that can be used to stimulate the first piezoelectricmaterial.